Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes

Xiaolin Ji; Lili Yao; Meihong Wang; Xiaoyu Liu; Su Peng; Kaixuan Li; Muchen Xu; Ningmei Shen; Lan Luo; Cheng Sun

doi:10.1016/j.febslet.2015.11.029

Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes

FEBS Lett. 2015 Dec 21;589(24 Pt B):3938-44. doi: 10.1016/j.febslet.2015.11.029. Epub 2015 Nov 22.

Authors

Xiaolin Ji¹, Lili Yao², Meihong Wang³, Xiaoyu Liu³, Su Peng³, Kaixuan Li¹, Muchen Xu⁴, Ningmei Shen⁴, Lan Luo⁵, Cheng Sun⁶

Affiliations

¹ Department of Geratology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
² Department of Endocrinology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
³ Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, People's Republic of China.
⁴ School of Medicine, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, People's Republic of China.
⁵ Department of Geratology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, People's Republic of China. Electronic address: chinaluolan@hotmail.com.
⁶ Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, People's Republic of China. Electronic address: suncheng1975@ntu.edu.cn.

PMID: 26592151
DOI: 10.1016/j.febslet.2015.11.029

Abstract

It has been reported that cystatin c (Cys C) closely correlates with metabolic disorders such as obesity and diabetes. However, it is still unknown whether Cys C plays a role for these disorders. Our results showed that the insulin signal transduction was largely impaired by Cys C in hepatocytes. In myotubes, however, the insulin signal transduction was not affected. Following experiments revealed that Cys C could induce endoplasmic reticulum stress (ER stress) in hepatocytes, whereas Cys C had no such an effect in myotubes. The alleviation of ER stress by 4-Phenyl butyric acid (4-PBA) restored the impaired insulin signal transduction in Cys C-treated hepatocytes. These results provided direct evidence that, by inducing ER stress, Cys C impairs insulin signal transduction in hepatocytes.

Keywords: Cystatin C; ER stress; Insulin signal transduction; Obesity; Type 2 diabetes; Unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Cell Line
Cells, Cultured
Cystatin C / antagonists & inhibitors
Cystatin C / blood
Cystatin C / genetics
Cystatin C / metabolism*
Diabetes Mellitus, Type 2 / blood
Diabetes Mellitus, Type 2 / metabolism
Down-Regulation* / drug effects
Endoplasmic Reticulum Stress* / drug effects
Gene Expression Regulation / drug effects
Hepatocytes / cytology
Hepatocytes / drug effects
Hepatocytes / metabolism*
Hepatocytes / pathology
Humans
Insulin / chemistry
Insulin / genetics
Insulin / metabolism*
Male
Mice, Inbred C57BL
Mice, Mutant Strains
Muscle Fibers, Skeletal / drug effects
Muscle Fibers, Skeletal / metabolism
Organ Specificity
Phenylbutyrates / pharmacology
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Signal Transduction* / drug effects
Up-Regulation / drug effects

Substances

Antineoplastic Agents
CST3 protein, human
Cst3 protein, mouse
Cystatin C
Insulin
Phenylbutyrates
Recombinant Proteins
4-phenylbutyric acid